TY  - JOUR
A1  - Ponnuswamy, Padmapriya
A1  - Schröttle, Angelika
A1  - Ostermeier, Eva
A1  - Grüner, Sabine
A1  - Huang, Paul L.
A1  - Ertl, Georg
A1  - Hoffmann, Ulrich
A1  - Nieswandt, Bernhard
A1  - Kuhlencordt, Peter J.
T1  - eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice
JF  - PLoS One
N2  - Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. 
Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels. 
Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects.
KW  - platelet adhesion
KW  - lesion formation
KW  - nitric oxide synthase
KW  - endothelial cell interactions
KW  - double knockout mice
KW  - apolipoprotein E
KW  - deficient mice
KW  - in vivo
KW  - accelerated atherosclerosis
KW  - leukocyte adhesion
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134866
VL  - 7
IS  - 1
ER  -